Pulmonary hypertension, a disease of multiple etiologies but poorly understood mechanisms, eventually leads to right ventricular hypertrophy, heart failure and often death. Recently, in a hypoxia-induced model of pulmonary hypertension, we found a gene that was highly upregulated, which we named hypoxia- induced mitogenic factor (HIMF). We found HIMF to be expressed in the remodeling PCNA positive pulmonary vessels and demonstrated that recombinant HIMF had mitogenic, angiogenic, vasoconstrictive and chemokine-like properties. HIMF/FIZZ1 is thus a novel candidate gene involved in the complex interplay between pulmonary vascular and right ventricular remodeling, a central focus of this SCCOR application. We hypothesize that HIMF is a polyvalent cytokine, which mediates critical lung cellular events in hypertensive pulmonary vascular remodeling, and is involved in the transition of adaptive to maladaptive right ventricle in pulmonary hypertension. Specific Aim #1 will examine the role of HIMF/FIZZ1 in the mechanism of pulmonary hypertension in animal models that emphasize hypoxia-related remodeling (chronic hypoxia exposure), inflammation (monocrotaline) and abnormal vessel growth (plexiform lesions and vascular remodeling associated with combined chronic hypoxia and VEGF2 receptor inhibition). Specific Aim #2 will use genomic, proteomic, and physiologic/pharmacologic approaches to examine HIMF effect on components of known downstream HIMF signaling pathways related to PAH and vascular remodeling including inflammation, growth factors/cell cycle activation, angio/vasculogenesis and reactive oxygen species generation in lung and heart. Specific Aim #3 will identify the HIMF receptor(s) and/or binding partners in lung and heart utilizing proteomics to identify its interactome network and post- translational modifications (PTMs) in lung and heart during the development of PAH. Specific Aim #4 will investigate the role and mechanism of HIMF inhibition in the protective and reversal actions of simvastatin and sildenafil on pulmonary vascular remodeling and right ventricular remodeling in models of PAH.